US11612647B2ActiveUtilityA1

Immunogenic compositions

Assignee: UNIV MARYLANDPriority: Jun 23, 2017Filed: Jun 22, 2018Granted: Mar 28, 2023

Est. expiryJun 23, 2037(~11 yrs left)· nominal 20-yr term from priority

Inventors:Donna M. Ambrosino Teresa J. Broering Alan Cross Richard Malley Francis Michon George Rainer Siber Raphael Simon Sharon Tennant

C07K 14/26A61K 39/104A61P 31/04A61K 2039/70A61K 39/40A61K 2039/6031C07K 14/21A61K 2039/55505C07K 14/245C07K 2319/00A61K 39/0266A61K 47/646A61K 39/0258A61K 2039/625A61K 2039/622C08B 37/0003A61K 39/116A61K 2039/6087Y02A50/30

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Claims

Abstract

Technologies for the prevention and/or treatment of nosocomial infections.

Claims

exact text as granted — not AI-modified

We claim:

1. A vaccine composition comprising:
(a) a first immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a P. aeruginosa (PA) O1 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer;
(b) a second immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O2 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer;
(c) a third immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O3 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer;
(d) a fourth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O4 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer;
(e) a fifth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O5 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer;
(f) a sixth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O6 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer;
(g) a seventh immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O10 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer; and
(h) an eighth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a PA O11 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer.

2. A pharmaceutical composition comprising the vaccine composition of claim 1 and a pharmaceutically acceptable carrier.

3. A method of immunizing a subject against Klebsiella infection and/or P. aeruginosa infection comprising administering to the subject an effective amount of the vaccine composition of claim 1 .

4. The vaccine composition of claim 1 , wherein the OPS in at least one of the immunogenic compositions is conjugated with a linker to the Klebsiella spp. K19 capsular polysaccharide.

5. The vaccine composition of claim 1 , wherein the Rhavi-FlaBD2-MrkA fusion protein comprises (i) a biotin-binding protein or biotin-binding domain thereof comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO: 14 (rhizavidin lacking signal sequences), (ii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:10 ( P. aeruginosa flagellin subtype B D2 domain (FlaBD2) lacking the TLR5 binding motif) or an immunogenic fragment thereof, and (iii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:2 or SEQ ID NO:3 ( K. pneumoniae MrkA) or an immunogenic fragment thereof.

6. The vaccine composition of claim 1 , wherein the Rhavi-FlaBD2-PcrV fusion protein comprises (i) a biotin-binding protein or biotin-binding domain thereof comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO: 14 (rhizavidin lacking signal sequences), (ii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:10 ( P. aeruginosa flagellin subtype B D2 domain (FlaBD2) lacking the TLR5 binding motif) or an immunogenic fragment thereof, and (iii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:8 ( P. aeruginosa PcrV) or an immunogenic fragment thereof.

7. The vaccine composition of claim 5 , wherein the Rhavi-FlaBD2-MrkA fusion protein is or comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 24.

8. The vaccine composition of claim 6 , wherein the Rhavi-FlaBD2-PcrV fusion protein is or comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 26.

9. The vaccine composition of claim 1 , further comprising at least one additional immunogenic composition that comprises: (i) a backbone polymer comprising a polymer and one or more antigenic polysaccharides conjugated to the polymer; and (ii) one or more polypeptide antigens non-covalently complexed with the polymer and/or the antigenic polysaccharide.

10. The vaccine composition of claim 9 , wherein the polymer of at least one of the additional immunogenic composition(s) is a capsular polysaccharide derived from a gram-negative or gram-positive bacteria.

11. The vaccine composition of claim 9 , wherein the polymer of at least one of the additional immunogenic composition(s) is a Klebsiella capsular polysaccharide, Pseudomonas exopolysaccharide, and/or Escherichia capsular polysaccharide.

12. The vaccine composition of claim 9 , wherein the polymer of at least one of the additional immunogenic composition(s) is a Klebsiella spp. K19 capsular polysaccharide.

13. The vaccine composition of claim 9 , wherein the polymer of at least one of the additional immunogenic composition(s) is a linear poly-L-lysine, or a dendrimer of L-lysine.

14. The vaccine composition of claim 9 , wherein the at least one additional immunogenic composition comprises:
(a) a backbone polymer comprising a polymer and one or more antigenic polysaccharides conjugated to the polymer;
(b) one or more polypeptide antigens; and
(c) at least one affinity-molecule pair comprising a first affinity molecule and a second affinity molecule complementary to the first affinity molecule;
wherein the backbone polymer is associated with the first affinity molecule;
wherein at least one of the polypeptide antigen(s) is associated with the second affinity molecule; and
wherein the first affinity molecule non-covalently complexes with the second affinity molecule to link the backbone polymer and the one or more polypeptide antigens.

15. The vaccine composition of claim 14 , wherein the affinity-molecule pair is selected from the group consisting of: biotin/biotin-binding protein, antibody/antigen, enzyme/substrate, receptor/ligand, metal/metal-binding protein, carbohydrate/carbohydrate binding protein, lipid/lipid-binding protein, and His tag/His tag-binding molecule.

16. The vaccine composition of claim 14 , wherein the first affinity molecule is or comprises biotin or a derivative thereof.

17. The vaccine composition of claim 14 , wherein the second affinity molecule is or comprises a biotin-binding protein or biotin-binding domain thereof.

18. The vaccine composition of claim 17 , wherein the biotin-binding protein is or comprises rhizavidin or a biotin-binding domain thereof.

19. The vaccine composition of claim 17 , wherein the biotin-binding protein or biotin-binding domain thereof is or comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO: 14 (rhizavidin lacking signal sequences).

20. The vaccine composition of claim 14 , wherein the first affinity molecule is cross-linked or covalently bonded to the polymer and/or the one or more antigenic polysaccharides, of the additional immunogenic composition.

21. The vaccine composition of claim 14 , wherein the second affinity molecule is associated with the one or more polypeptide antigens of the additional immunogenic composition to form a fusion protein.

22. The vaccine composition of claim 21 , wherein the fusion protein comprises (i) a biotin-binding protein or biotin-binding domain thereof, and (ii) the one or more polypeptide antigens.

23. The vaccine composition of claim 22 , wherein the one or more polypeptide antigens are each independently selected from the group consisting of: P. aeruginosa flagellin subtype B D2 domain (FlaBD2) lacking the TLR5 binding motif, P. aeruginosa PcrV, K. pneumoniae MrkA, and immunogenic fragments thereof.

24. The vaccine composition of claim 22 , wherein the one or more polypeptide antigens are each independently selected from the group consisting of: a P. aeruginosa flagellin subtype A, P. aeruginosa flagellin subtype B, and immunogenic fragments thereof.

25. The vaccine composition of claim 21 , wherein the fusion protein comprises (i) a biotin-binding protein or biotin-binding domain thereof, (ii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:10 ( P. aeruginosa flagellin subtype B D2 domain (FlaBD2) lacking the TLR5 binding motif) or an immunogenic fragment thereof, and (iii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:2 or SEQ ID NO:3 ( K. pneumoniae MrkA) or an immunogenic fragment thereof.

26. The vaccine composition of claim 21 , wherein the fusion protein comprises (i) a biotin-binding protein or biotin-binding domain thereof, (ii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:10 ( P. aeruginosa flagellin subtype B D2 domain (FlaBD2) lacking the TLR5 binding motif) or an immunogenic fragment thereof, and (iii) a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of SEQ ID NO:8 ( P. aeruginosa PcrV) or an immunogenic fragment thereof.

27. The vaccine composition of claim 25 , wherein the fusion protein is or comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 24.

28. The vaccine composition of claim 26 , wherein the fusion protein is or comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 26.

29. The vaccine composition of claim 9 , wherein the one or more antigenic polysaccharides of at least one of the additional immunogenic composition(s) comprise a polysaccharide of one or more of Klebsiella, Pseudomonas , and E. coli.

30. The vaccine composition of claim 9 , wherein the one or more antigenic polysaccharides of at least one of the additional immunogenic composition(s) comprise a K. pneumoniae OPS of type O1, O2, O3, O5, or a combination thereof.

31. The vaccine composition of claim 9 , wherein the one or more antigenic polysaccharides of at least one of the additional immunogenic composition(s) comprise a P. aeruginosa OPS of type O1, O2, O3, O4, O5, O6, O10, O11, O12, or a combination thereof.

32. The vaccine composition of claim 9 , wherein the at least one additional immunogenic composition comprises:
(a) a backbone polymer comprising:
(i) a polymer comprising a Klebsiella spp. K19 capsular polysaccharide; and
(ii) one or more antigenic polysaccharides comprising a polysaccharide of Klebsiella or Pseudomonas conjugated to the Klebsiella spp. K19 capsular polysaccharide;

(b) one or more polypeptide antigens; and
(c) at least one affinity-molecule pair comprising a first affinity molecule and a second affinity molecule complementary to the first affinity molecule;
wherein the polymer is associated with the first affinity molecule;
wherein at least one of the polypeptide antigen(s) is associated with the second affinity molecule; and
wherein the first affinity molecule non-covalently complexes with the second affinity molecule to link the polymer and the one or more polypeptide antigens.

33. The vaccine composition of claim 32 , further comprising:
(a) a ninth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a KP O1 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer;
(b) a tenth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a KP O2 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer;
(c) an eleventh immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a KP O3 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-MrkA fusion protein non-covalently complexed to the biotinylated backbone polymer; and
(d) a twelfth immunogenic composition comprising a backbone polymer comprising a polymer comprising a biotinylated Klebsiella spp. K19 capsular polysaccharide, a KP O5 OPS conjugated to the Klebsiella spp. K19 capsular polysaccharide, and a Rhavi-FlaBD2-PcrV fusion protein non-covalently complexed to the biotinylated backbone polymer.

34. The pharmaceutical composition of claim 2 , further comprising one or more adjuvants.

35. The pharmaceutical composition of claim 34 , wherein at least one of the adjuvant(s) is selected from the group consisting of: aluminum phosphate, aluminum hydroxide, phosphate aluminum hydroxide, a TLR agonist, and combinations thereof.

36. The pharmaceutical composition of claim 2 , wherein the composition is formulated for injection.

37. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is characterized in that upon administration to a subject, the pharmaceutical composition elicits (i) a Th1 and/or Th17 cell response; and/or (ii) an opsonic/bactericidal response against Klebsiella and/or Pseudomonas.

38. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is characterized in that upon administration to a subject, the pharmaceutical composition reduces rate of transmission and/or colonization of the mucosal surfaces and/or the GI tract by Klebsiella and/or Pseudomonas.

39. The method of claim 3 , wherein upon administration to the subject, the vaccine composition elicits (i) a Th1 and/or Th17 cell response; and/or (ii) an opsonic/bactericidal response against Klebsiella and/or Pseudomonas.

40. The method of claim 3 , wherein upon administration to the subject, the vaccine composition reduces rate of transmission and/or colonization of the mucosal surfaces and/or the GI tract by Klebsiella and/or Pseudomonas.

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